DESCRIPTION: To create an animal model system in which the infecting virus more closely resembles HIV-1, chimeric viruses containing genetic elements of HIV-1 (tat, rev, vpu, env) in a background of SIVmac were constructed. Unlike HIV-1, these chimeric simian-human immunodeficiency viruses (SHIV) infect a variety of monkey species and elicit cellular and humoral immune responses similar to those observed in HIV-1 infected humans. An animal-passaged SHIV variant containing the envelope glycoproteins of a primary patient HIV-1 isolate can deplete CD4+ lymphocytes in rhesus monkeys in a rapid and specific fashion. In this competing renewal application, Dr. Sodroski proposes the following Specific Aims: Specific Aim 1: To obtain and characterize the pathogenic molecular clone SHIV. Specific Aim 2: To characterize viral and host variables that affect in vivo SHIV replication and pathogenicity. Specific Aim 3: To construct and assess in vivo additional SHIVs with env and pol replacements. SHIV chimerics with diverse envelop glycoproteins from primary HIV-1 isolates as well as SHIV constructs containing the reverse transcriptase of HIV 1 will be studied. Specific Aim 4: To examine the role of HIV-1 specific Vpu protein in SHIV replication and pathogenicity.